2′-C-Alkylribonucleosides have been described in the patent literature as inhibitors of HCV RNA-dependent RNA polymerase and thereby useful for the treatment of HCV infection. Reference is made to the following publications of international patent applications which disclose branched-chain ribonucleoside inhibitors of HCV polymerase: WO 01/90121 (29 Nov. 2001) and WO 01/92282 (6 Dec. 2001) both assigned to Novirio Pharmaceuticals and Universita degli Studi di Cagliari; WO 02/32920 (25 Apr. 2002) assigned to Pharmasset Limited; and WO 02/057287 (25 Jul. 2002) and WO 02/057425 (25 Jul. 2002) assigned jointly to Merck & Co. and Isis Pharmaceuticals. Synthetic approaches to 2′-C-branched ribonucleosides have previously been described in the chemical and patent literature: FR 1521076 (12 Apr. 1968); U.S. Pat. No. 3,480,613 (25 Nov. 1969); GB Patent No. 1209654 (21 Oct. 1970); S. R. Jenkins et al. Carbohydrate Res., 166: 219-232 (1987); A. Matsuda et al., Chem. Pharm. Bull., 36: 945-953 (1988); M. S. Wolfe et al., “A Concise Synthesis of 2′-C-Methylribonucleosides,” Tetrahedron Lett., 42: 7611-7614 (1995); R. E. Harry-O'kuru et al., “A Short, Flexible Route toward 2′-C-branched Ribonucleosides,” J. Org. Chem., 62: 1754-1759 (1997); Y. Murai et al., “A Synthesis and X-Ray Analysis of 2′-C-, 3′-C-, and 5′-C-Methylsangivamycins,” Heterocycles, 33: 391-404 (1992); J. Wolf et al., Synthesis, 773-778 (1992); and M. Gallo et al., “Synthesis of 2′-Modified Nucleotides,” Molecules, 5: 727-729 (2000). Although the synthetic methods disclosed in these references suffice to prepare small quantities of the desired branched-chain ribonucleosides, they suffer from low and variable yields in the key glycosylation step to elaborate the nucleosidic bond in a stereoselective fashion and therefore are not amenable from an economic perspective to scale-up for the production of kilogram quantities required for preclinical and clinical use.
The present invention provides a novel process for the preparation of 2′-C-alkylribonucleosides which are inhibitors of HCV polymerase useful for the treatment of HCV infection.